Major depressive disorder (MDD) is a greatly debilitating illness affecting a large number of individuals. Cortical and subcortical brain dysfunctions play a role in the pathophysiology of MDD, but the neurophysiology of the regulation of mood in health and disease remains largely unclear. A deeper understanding about the neuroregulation of mood and its dysfunction in depression would help improve treatment of MDD. Currently, treatment of MDD is not always successful and is frequently associated with unpleasant side-effects. The development of a safer therapy for depression, specially for medication-resistant forms, with fewer side-effects would be greatly desirable. In the last few years, several studies suggest that non-invasive, non-convulsive repetitive transcranial magnetic stimulation (rTMS) is a useful tool in the study of the neural organization of mood and emotion in health and disease and furthermore, that rTMS of the left prefrontal cortex has a therapeutic potential in MDD. However, the mechanisms of action of rTMS remain largely unclear and the potential side-effects of this technique have not been systematically explored. We propose the systematic study of the effects on mood and the safety of different rTMS settings. Effects of rTMS in depressed patients and in normal volunteers will be compared in order to enhance our understanding about the neuroregulation of emotion. In depressed patients, the antidepressant effects of rTMS might primarily be due to an increase in left prefrontal cortical activity, thus normalizing the interhemispheric prefrontal activity balance by rather different mechanisms than ECT. This hypothesis will be tested by correlating the mood effects of the different rTMS parameters with their effects onto cortical excitability and regional cortical cerebral blood flow evaluated with single photon emission tomography (SPECT). Studies of the effects of different rTMS parameters on a battery of neuropsychological and neurochemical tests will further illustrate the mechanisms of action of rTMS and address potential side effects. These studies will lead to the development of a safe method of non-convulsive rTMS for MDD, grounded on a deeper understanding of the mechanisms of action of rTMS and the neuroregulation of emotion. In case that the antidepressant effects of rTMS suggested by previous studies are ratified in the present project, this method will then be testable in future studies comparing rTMS with other treatment modalities of depression.